JP2848552B2 - Crystalline carbapenem derivatives - Google Patents

Abstract

A storage stable form of the pivaloyloxymethyl ester of the carbapenem derivative known as (1R, 5S, 6S)-2-[(4R)-2-oxo-4-pyrrolidinylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl -1-carbapen-2-em-3-carboxylic acid in crystalline form. <IMAGE>

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a crystal of a carbapenem compound useful as a pharmaceutical antibacterial compound and an antibacterial agent containing the same.

[0002]

2. Description of the Related Art The inventors have previously disclosed in Japanese Patent Application Laid-Open No. 2-49783 a formula.

[0003]

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[0004] A 1-methylcarbapenem derivative having the formula: This is an oral carbapenem compound having excellent antibacterial activity not only against gram-negative bacteria but also against gram-positive bacteria by oral administration, and its practical use is being studied. In order to make this a practical drug, it must be easy to handle and stable under ordinary conditions. The present inventors have conducted various studies and found that the compound of the present invention can be obtained as stable crystals, and have completed the present invention.

[0005]

[Means for Solving the Problems]

[0006]

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The present invention relates to crystalline (1R, 5S, 6) having the above formula.
S) -2-[(4R) -2-oxo-4-pyrrolidinylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid Pivaloyloxymethyl ester, and the crystals have λ = 1.
In powder X-ray diffraction obtained by irradiation of copper with a wavelength of 54 ° by Kα ray, the interplanar spacings were 18.41, 9.21, 6.24, 5.28, 5.04, 4.7
2Å shows the main peak. The crystalline compound of the present invention comprises (1)
R, 5S, 6S) -2-[(4R) -2-oxo-4-pyrrolidinylthio] -6-[(1R) -1-hydroxyethyl]-
The sodium salt of 1-methyl-1-carbapen-2-em-3-carboxylic acid (JP-A-2-49783) is reacted with pivaloyloxymethyl iodide, and the reaction mixture is diluted with ethyl acetate and washed with water. Concentrate, dissolve the residue in dichloromethane as a good solvent, add ethanol as a poor solvent or dissolve in a mixed solvent of dichloromethane and ethanol and leave as it is Can obtain a crystal.
The ratio of dichloromethane to ethanol may be sufficient if it is sufficient for crystallization, but is preferably about 1: 1 to 1: 4. The obtained crystals are washed, dried and isolated by a conventional method.
The crystals of the present invention thus obtained have a melting point of about 189 ° C., and are determined by X-ray powder diffraction to have plane spacings of 18.41, 9.21, 6.24,
FIG. 3 shows diffraction patterns having main peaks of 5.28, 5.04, and 4.72 °.

[0008] Solvents used for crystallization of the residue obtained from the reaction solution include, as good solvents, halogenated hydrocarbons such as dichloromethane, dialkyl sulfoxides such as dimethyl sulfoxide, dimethylformamide and dimethylacetamide. Amides, alcohols such as methanol, and poor solvents include ethers such as ethanol, water, acetone and diethyl ether, esters such as ethyl acetate, and hydrocarbons such as cyclohexane and benzene. Can be

[0009]

Industrial Applicability The crystal of the present invention is a stable crystal which is practically easy to handle and is an antibiotic which shows a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria and cephalosporinase-producing bacteria by oral administration. Useful. Its antibacterial activity was measured in horse serum at 37 ° C. for 1 hour and its activity was measured by an agar plate dilution method. For example, Gram-positive bacteria such as Staphylococcus aureus and Enterococcus, Escherichia coli, Shigella, and Klebsiella pneumoniae ,
It showed potent activity against a wide range of pathogens, including gram-negative bacteria such as deformed bacteria, Serratia, Enrobacter, and Pseudomonas aeruginosa, and anaerobic bacteria such as Bacteroides fragilis. When the crystals of the present invention were orally administered to mice, they showed a high urine recovery rate, and further showed excellent therapeutic effects by oral administration in systemic infection of mice with Staphylococcus aureus and Escherichia coli. Therefore, the crystals of the present invention are useful as oral antibacterial agents for treating bacterial infections caused by these pathogenic bacteria.

The crystals of the present invention are used as an active ingredient in an ordinary pharmaceutical method, for example, excipients such as starch, lactose, sucrose, calcium carbonate, calcium phosphate, polyethylene glycol, etc., for example, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinyl Binders such as pyrrolidone, for example, lubricating agents such as magnesium stearate, talc, sodium lauryl sulfate, polyethylene glycol, for example, disintegrating agents such as calcium carboxymethylcellulose, alginic acid or a salt thereof, coloring agents, flavors, sweeteners and the like. By mixing with various additives and the like, oral preparations such as capsules, powders, granules and tablets can be produced. The dose varies depending on age, body weight, symptoms, etc., but is about 50 mg to 2 mg / day for adults.
g, and can be given in 2 to 4 divided doses.

Now, the present invention will be described in further detail with reference to Examples, Test Examples and Reference Examples. The nuclear magnetic resonance spectra in Examples and Reference Examples were measured using tetramethylsilane as an internal standard or an external standard unless otherwise specified.

[0012]

【Example】

Embodiment 1 FIG. (1R, 5S, 6S) -2-[(4R) -2-oxo-
4-pyrrolidinylthio] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapen-2-em-
3-Carboxylic acid pivaloyloxymethyl ester Compound (1R, 5S, 6S) -2- described in JP-A-2-49783
[(4R) -2-oxo-4-pyrrolidinylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1-
Carbapen-2-em-3-carboxylic acid sodium salt (4.76 g) was dissolved in N, N-dimethylacetamide (35 ml), and pivaloyloxymethyl iodide (3.60 g) was added under ice-cooling for 30 minutes. Stirred. This was diluted with ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The powdery residue (4.54 g) was dissolved in ethanol-dichloromethane (1: 1), and dichloromethane was distilled off under reduced pressure to precipitate crystals. This was collected by filtration and dried to give the target compound (3.86 g) as colorless crystals. Melting point 189 ° C Infrared absorption spectrum (KBr) νcm ^-1 : 3336, 1764, 175
1, 1717, 1691, 1542, 1347, 1213, 1160, 1114, 995. Ultraviolet absorption spectrum (CH ₃ CN) λmax nm: 324 Nuclear magnetic resonance spectrum (DMSO-d ₆ , 400MHz, internal standard tetramethylsilane) δppm: 1.10-1.18 (15H, m), 2.11 (1H, dd, J = 17.0 and 4.
3Hz), 2.78 (1H, dd, J = 17.0 and 7.7Hz), 3.09 (1H, dd, J = 1
0.9 and 3.9Hz), 3.25 (1H, dd, J = 6.2 and 2.5Hz), 3.44-
3.48 (1H, m), 3.71 (1H, dd, J = 10.9 and 7.6Hz), 3.94-4.0
0 (1H, m), 4.04-4.09 (1H, m), 4.23 (1H, dd, J = 9.5 and 2.5
Hz), 5.08 (1H, d, J = 5.1Hz), 5.73 (1H, d, J = 5.9Hz), 5.88
(1H, d, J = 5.9Hz), 7.84 (1H, s). X-ray powder diffraction pattern: FIG. 1 shows the diffraction pattern.

[0013] [Test Example] The amorphous form powder obtained by the method described in JP-A-2-49783 discloses a crystalline form powders and control of esters prepared by the process of the present invention 60 ° C. - stored on a silica gel desiccator Then, the residual ratio after 7 days (1 week) and 28 days (4 weeks) was measured.

Method for Measuring Residual Rate (%) The residual amount of the ester compound was measured by high performance liquid chromatography (HPLC).

Column: Inertsil ODS-2 (4.6 mmφ × 150 mm) Mobile phase: 20 mM 3- (N-morpholino) propanesulfonic acid buffer (pH 7): CH ₃ CN = 70: 30 Detection: UV, 322 nm

[0016]

[Table 1]

(1R, 5S, 6S) -2- obtained by the present invention
[(4R) -2-oxo-4-pyrrolidinylthio] -6
[(1R) -1-hydroxyethyl] -1-methyl-1-
The crystals of carbapene-2-em-3-carboxylic acid pivaloyloxymethyl ester have excellent storage stability, as shown in Table 1, and are therefore useful as oral antibacterial agents.

Reference Example 1 (4S) -2-oxo-4-hydroxypyrrolidine (1) Ethyl (S) -4-chloro-3-hydroxybutyrate (5.0 g), sodium iodide (900 mg), ammonia (11.6 g) ) -Methanol (50 ml) was heated in a stainless steel autoclave at 80 ° C for 3 hours. Reaction solution at 0-5 ° C
After cooling, the solvent was distilled off. The residue was subjected to column chromatography using silica gel, and chloroform-
The solid was developed with methanol (5/1) to give the title compound (2.97 g) as crystals. Melting point 158-161 ° C Optical rotation [α] _D ²⁴ −55. ²⁴ ° (C = 1.0, H ₂ O) Infrared absorption spectrum ν _max ^KBr cm ^-1 : 3247,3145,167
2,1483,1446,1416 Nuclear magnetic resonance spectrum (400 MHz, D ₂ O, internal standard sodium trimethylsilylpropionate-d ₄ ) δppm: 2.28 (1
H, dd, J = 17.72,1.64Hz), 2.77 (1H, dd, J = 17.72,6.72Hz), 3.
34 (1H, dd, J = 11.75,1.03Hz), 3.72 (1H, dd, J = 11.75,5.21H
z), 4.60-4.64 (1H, m).

(2) Ethyl (S) -4-chloro-3-hydroxybutyrate (5.0 g) and ammonia (11.6 g) -methanol (50 ml) in a stainless steel autoclave at 100 ° C. Heat for 5 hours. The reaction solution was treated and purified in the same manner as in (1) to give the title compound as crystals (2.65 g). This was in agreement with that obtained in (1) in melting point, optical rotation and nuclear magnetic resonance spectrum.

(3) 29% aqueous ammonia was added to (S) -4-chloro-3-hydroxybutyronitrile (2.5 g), and the mixture was heated in a stainless steel autoclave at 120 ° C. for 8 hours.
The reaction solution was treated and purified in the same manner as in (1) to obtain the title compound as crystals (1.2 g). This was in agreement with that obtained in (1) in melting point, optical rotation and nuclear magnetic resonance spectrum.

Reference Example 2 (4S) -2-oxo-4-methanesulfonyloxypyrrolidine (1) (4S) -2-oxo-4-hydroxypyrrolidine (1.90 g) was dissolved in pyridine (100 ml), and cooled with ice. Under stirring, methanesulfonyl chloride (2.26 g) was added dropwise.
After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. Aqueous sodium hydrogen carbonate (9 ml) was added to the residue, and the mixture was again concentrated to dryness. Ethyl acetate-methanol (1: 1:
1) was added, the insoluble portion was removed by filtration, and the soluble portion was concentrated. The residue obtained from the soluble portion was subjected to silica gel column chromatography (Merck 9385, 150 ml) to give ethyl acetate-
It was developed with methanol (9: 1 → 4: 1). The crystalline residue obtained by combining and concentrating the target fractions was recrystallized from ethyl acetate-methanol to give crystalline (4S) -2-oxo-4-methanesulfonyloxypyrrolidine (2.44
g) was obtained. Melting point 137.5-139 ° C Optical rotation [α] _D ²⁴ −35.5 ° (C = 1.09, MeOH) Infrared absorption spectrum ν _max ^KBr cm ^-1 : 1719, 1697,
1659, 1305, 1177, 1171, 1159, 963. Nuclear magnetic resonance spectrum (400MHz, DMSO-d ₆ ) δppm: 2.28
(1H, dd, J = 17.6, 1.8Hz), 2.71 (1H, dd, J = 17.6, 6.3Hz),
3.24 (3H, s), 3.37 (1H, d, J = 11.9Hz), 3.66 (1H, dd, J = 11.
9, 5.3Hz), 5.31-5.34 (1H, m), 7.85 (1H, bs).

(2) Ethyl (S) -4-chloro-3-hydroxybutyrate (5.0 g), sodium iodide (900 mg), ammonia (11.6 g) -methanol (50 ml) were added to a stainless steel autoclave. After heating in the same manner at 80 ° C. for 3 hours, pyridine (300 ml) was added to the crude product obtained by evaporating the solvent, methanesulfonyl chloride (2.26 g) was added dropwise at 0-5 ° C., and the mixture was heated to the same temperature. After stirring for 2 hours, sodium hydrogen carbonate (4.2 g) -water (100 ml) was added, and the mixture was concentrated to dryness. The residue is treated and purified in the same manner as in (1), and the crystalline title compound is obtained.
(2.7 g) was obtained. This was in agreement with that obtained in (1) in melting point, optical rotation and nuclear magnetic resonance spectrum.

Reference Example 3 (4R) -4-acetylthio-
2-oxopyrrolidine (1) (4S) -2-oxo-4-methanesulfonyloxypyrrolidine (896 mg) was added to anhydrous acetonitrile (90 m
l), add potassium thioacetate (857 mg),
The mixture was heated and refluxed on an oil bath at 85 ° C. for 2 hours. The insolubles were removed by filtration from the reaction solution, and the filtrate was concentrated. Ethyl acetate was added to the residue,
After filtering off the insoluble matter, the soluble portion was subjected to silica gel column chromatography, and ethyl acetate-methanol (1: 0).
→ 98: 2 → 96: 4 → 94: 6). The desired fractions were combined and concentrated to give a crystalline residue (593 mg).
This was recrystallized from ethyl acetate-cyclohexane to give the title compound (455 mg) as crystals. Melting point 59-60 ° C Optical rotation [α] _D ²⁵ + 47.3 ° (C = 1.33, MeOH) Infrared absorption spectrum ν _max ^KBr cm ^-1 : 1689, 1125. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 2.30 (1
H, dd, J = 17.4, 6.0Hz), 2.35 (3H, s), 2.80 (1H, dd, J = 17.4,
9.1Hz), 3.31 (1H, dd, J = 10.2, 5.1Hz), 3.89 (1H, dd, J = 1
0.2, 7.2Hz), 4.15-4.23 (1H, m), 7.27 (1H, bs).

(2) (4S) -2-oxo-4-hydroxypyrrolidine (380 mg) was suspended in anhydrous tetrahydrofuran (21 ml), and triphenylphosphine (1.18 g) was added at room temperature. Then diethyl azodicarboxylate (783 mg) was added dropwise. The temperature was gradually raised to 4 ° C., and the mixture was stirred at the same temperature for 30 minutes to obtain a uniform reaction solution. The reaction was cooled again to -20 ° C and thioacetic acid (32
0 μl) was added dropwise. The temperature was gradually raised to the ice-cooling temperature, and the mixture was stirred under the same conditions for 1.5 hours. The reaction solution was concentrated, subjected to silica gel column chromatography (Merck 9385, 60 ml), and developed with benzene-acetonitrile (2: 1 → 1: 1). The desired fraction was concentrated to give a crystalline residue (69 mg). Recrystallized using ethyl acetate-cyclohexane,
The title compound was obtained as crystals (54 mg).

This compound was found to have a melting point, optical rotation, infrared absorption spectrum and nuclear magnetic resonance spectrum, and
-Completely consistent with the compound obtained in (1).

(3) 2-oxo-4-hydroxypyrrolidine (1011 mg) was dissolved in pyridine (50 ml), and (1)
S) -10-Camphorsulfonic acid chloride (2.63 mg) was added under ice cooling, and the mixture was stirred under the same conditions for 10 minutes and at room temperature for 30 minutes. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, and washed with brine. The ethyl acetate layer was concentrated and subjected to silica gel column chromatography (Merck 9385, 100 ml) to give ethyl acetate-methanol (1: 0 → 95: 5 → 9:
Expanded in 1). The desired fraction was concentrated, dissolved in 50 ml of ethyl acetate and allowed to stand. The precipitated crystals were collected by filtration and dried to give (4S) -2-oxo-4-[(1S) -10-camphasulfonyloxy] pyrrolidine (262 mg). Melting point 114-116 ° C Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δppm: 0.89 (3
H, s), 1.10 (3H, s), 1.47 (1H, ddd, J = 12.5, 9.2, 3.3Hz),
1.70 (1H, ddd, J = 13.8,9.2,4.6Hz), 1.97 (1H, d, J = 17.5
Hz), 2.02-2.17 (2H, m), 2.35-2.49 (2H, m), 2.63 (1H, d
d, J = 17.8, 2.6Hz), 2.79 (1H, dd, J = 17.8, 6.6Hz), 3.05
(1H, d, J = 15.0Hz), 3.61 (1H, d, J = 15.0Hz), 3.66 (1H, d, J = 1
1.9Hz), 3.82 (1H, dd, J = 11.9, 6.0Hz), 5.43-5.48 (1H,
m), 6.01 (1H, bs) This compound (160mg) was dried with acetonitrile (16ml)
, And add potassium thioacetate (90mg), 90 ℃
And heated to reflux for 5 hours on an oil bath. The reaction solution was prepared in Reference Example 3-
Treated in the same manner as in (1), and crystallized the title compound (61 mg)
I got This compound has a melting point, an optical rotation, an infrared absorption spectrum and a nuclear magnetic resonance spectrum, which are referred to in Reference Example 3-
It completely matched the compound obtained in (1).

Reference Example 4 (4R) -2-oxo-4-mercaptopyrrolidine (4R) -2-oxo-4-acetylthiopyrrolidine (375 mg) was dissolved in methanol (5 ml), and the solution was cooled under ice-cooling.
N sodium methylate-methanol solution (2.35 ml) was added. After stirring for 20 minutes under the same conditions, 1N hydrochloric acid (2.35
ml) and concentrated to dryness. The ethyl acetate-soluble portion was concentrated to give the title compound as crystals (275 mg). Melting point 69.5-70 ° C Optical rotation [α] _D ²⁴ + 36.5 ° (C = 1.18, MeOH) Infrared absorption spectrum ν _max ^KBr cm ^-1 : 2539, 1699,
1683. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δppm: 1.96 (1
H, d, J = 7.2Hz), 2.32 (1H, dd, J = 17.2, 6.8Hz), 2.80 (1H, d
d, J = 17.2, 8.2Hz), 3.32 (1H, dd, J = 10.2, 5.6Hz), 3.62-
3.70 (1H, m), 3.81 (1H, dd, J = 10.2, 7.3Hz), 7.27 (1H, b
s).

Reference Example 5 (1R, 5S, 6S) -2-[(4R)
-2-oxo-4-pyrrolidinylthio] -6-[(1
R) -1- hydroxyethyl] -1-methyl-1-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (1R, 5 R, 6S) -2- diphenyl phosphoryl-6-
[(1R) -1-hydroxyethyl] -1-methyl-1
-Carbapene-2-M-3-carboxylic acid 4-nitrobenzyl ester (1000 mg) was added to acetonitrile (10 m
l) and dissolved in ice-cooled (4R) -2-oxo-4-mercaptopyrrolidine (200 mg) in acetonitrile (3 ml).
l) The solution and diisopropylethylamine (296 μl) were added. After stirring for 1 hour under the same conditions, the mixture was allowed to stand at 4 ° C. overnight. The crystalline compound precipitated from the reaction solution was collected by filtration and dried to obtain the title compound (672 mg).

The melting point and NMR spectrum of this compound were consistent with those of the compound described in Example 15 of JP-A-2-49783.

Reference Example 6 (1R, 5S, 6S) -2-[(4R)
-2-oxo-4-pyrrolidinylthio] -6-[(1
R) -1-Hydroxyethyl] -1-methyl-1-carbapene-2-em-3-carboxylate sodium compound (390 mg) obtained in Reference Example 5 was added to tetrahydrofuran (19 ml) and 0.1 M phosphate buffer (18 ml). ), 10% palladium on carbon catalyst (300 mg) was added, and the mixture was vigorously stirred in hydrogen gas for 2.5 hours. The catalyst was filtered off from the reaction solution, and the filtrate was washed twice with ether. The aqueous layer was concentrated under reduced pressure, MCI GEL CHP-20P (MITSUBISHI KASEI C O
RPORATION, 75-150 μm, 50 ml) and developed with water. The desired fraction was concentrated and lyophilized to give the title compound (225 mg) as a colorless powder. The NMR spectrum of this compound was consistent with that of the compound of Example 15 described in JP-A-2-49783.

[Brief description of the drawings]

FIG. 1: (1R, 5S, 6S) -2-[(4R) -2-oxo-4-
Pyrrolidinyloxy] -6-[(1R) -1-hydroxyethyl] -1-methyl-1-carbapene-2-em-3
-Powder X of pivaloyloxymethyl carboxylate X
It is a line diffraction pattern. The vertical axis indicates the diffraction intensity in cps units, and the horizontal axis indicates the value of the diffraction angle 2θ.

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Rokuro Endo 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) References JP-A-2-49783 (JP, A)

Claims (2)

(57) [Claims] (1) Formula (1) , And the surface intervals are 18.41, 9.21, 6.24, and 5.
(1R, 5S, 6S) -2- having X-ray diffraction patterns showing major peaks at 28, 5.04 and 4.72 °
[(4R) -2-oxo-4-pyrrolidinylthio] -6
-[(1R) -1-hydroxyethyl] -1-methyl-
Crystals of 1-carbapene-2-em-3-carboxylic acid pivaloyloxymethyl ester. 2. An active ingredient exhibiting antibacterial activity as claimed in claim 1.
An antibacterial agent containing only the crystals described in 1.